Ocular effects of autoimmunity

Peter J. McDonnell, MD, discusses how we are eight ways closer to understanding how diseases arise, which could pave the way for new treatments.

Autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and Sjogren’s syndrome afflict an estimated 100 million persons worldwide. As an ophthalmologist, I detest these problems because they frequently cause eye disease; their etiology remains a mystery, and our therapeutic outcomes are often disappointing.

Corticosteroids represent a blunt tool to try to minimize the suffering these bodies endure from their traitorous immune systems and pile on with their well-known side effects. Adding an expensive monoclonal antibody to the marinade might or might not prove helpful in some patients, but any amelioration of the disease certainly comes at the expense of yet more potential therapy-induced adverse reactions.

With dry eye disease in particular, which commonly occurs in the setting of Sjogren’s syndrome, our therapies are substantially better than those used to treat systemic autoimmune disease. Topical corticosteroids often improve signs and symptoms, and we have two FDA-approved agents that work by reducing the injurious effects of T-cells on the lacrimal gland and ocular surface.

Getting closer to understanding

Mountains of data generated by genetic analysis and analyzed by bioinformatics experts using supercomputers are pointing to a potential culprit: Epstein-Barr virus (EBV, HHV-4). A few tantalizing facts:

• After initial exposure, the virus can hide in our bodies at levels too low for our host defense mechanisms to detect and eradicate.
• People who have been infected with EpsteinBarr virus but are otherwise normal have >2% of their T cells reacting to the virus.  As two experts recently observed: “With the tens of thousands of organisms against which the ordinary person must continually defend themselves, this is an astonishingly high proportion of the host’s T cell repertoire.”
• EB infection increases a child’s risk of developing systemic lupus erythematosus by 50-fold.
• Patients with Sjogren’s syndrome have “ectopic lymphoid structures” in their salivary glands and these serve as a unique home for EpsteinBarr virus latency and subsequent reactivation.
• A recent paper in the journal Nature shows that a protein produced by EB virus-infected cells (EBNA2) binds to nearly half of the chromosomal loci known to increase the risk of development of systemic lupus erythematosus.
• Similar EBNA2 binding to DNA risk alleles with effects on gene expression are shown to exist in multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis and celiac disease.
• Acting as a transcription factor, this viral EBNA2 protein regulates gene expression in a manner that appears to explain much of the risk related to the development of these important and common autoimmune diseases.
• There are drugs available that have the ability to bind to and inhibit the EBNA2 protein.

This indicates that, if EB infection is the inciting mechanism for Sjogren’s syndrome and these other autoimmune disease, it may be possible to block the virus-generated protein from interacting with our human chromosomes and condemning patients to a lifelong struggle with one of these terrible problems.

Future ophthalmologists will no doubt look back at how we treat many patients today and shake their heads at our ignorance. Every generation of doctors does this. Wouldn’t it be great to know why so many people are afflicted with diseases like Sjogren’s syndrome and have a new, specific way to treat them?

Peter J. McDonnell, MDDirector of the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, and chief medical editor of Ophthalmology Times. He can be reached at 727 Maumenee Building 600 N. Wolfe St. Baltimore, MD 21287-9278Phone: 443/287-1511 Fax: 443/287-1514E-mail: pmcdonn1@jhmi.edu